The present invention relates to a process for the halogenation of activated methylene or methine groups of organic compounds with electrophilic halogenating reagents, in which said organic compounds are reacted in the presence of catalytic amounts of a titanium tetrahalide or of an alcoholate-containing titanium(IV) trihalide or titanium(IV) dihalide with an electrophilic halogenating reagent; to a process for the enantioselective halogenation of an activated methine group of organic compounds with electrophilic halogenating reagents, in which said organic compounds are reacted in the presence of catalytic amounts of a chiral 1,3-, 1,4- or 1,5-diolate-containing titanium(IV) dihalide with a halogenating reagent.
Fluorine-substituted organic compounds have recently attracted increased interest as active pharmaceutical ingredients and pesticides. The fluorination frequently employs electrophilic fluorination reagents with which it is possible to replace hydrogen atoms in aromatic, olefinically unsaturated or activated aliphatic intermediates or final products. Large numbers of electrophilic fluorination reagents are known. Besides fluorine, those most frequently used are mainly inert gas fluorides, oxyfluorides, N-fluorinated pyridinium salts, tertiary N-fluoroammonium salts and N-fluorinated imides. A review of fluorination reagents is to be found, for example, in Chem. Rev. 1996, 96,1717-1736 by S. Rozen, and in Chem. Rev. 1996, 96, 1737 to 1755 by G. Sanker Lal et al.
The fluorination of carbon acids is generally known and is described, for example, in review articles in Houben-Weyl, 1999, volume E 10a, pages 433 to 499, by S. D. Taylor in Tetrahedron 55,1999, pages 12431 to 12477, and by F. A. Davis in Organic Preparations and Procedures Int., 1999, 31(2), pages 125-143. The fluorination is usually carried out with previous formation of carbanions or enolates by adding alkali metal amides or other strong bases.
Direct fluorinations of keto compounds have also been reported recently. T. Umemoto et al. describe in J. Org. Chem. 1995, 60, pages 6563 to 6570 the fluorination of xcex2-diketo compounds with N-fluoro-4,6-trifluoromethylpyridinium-3-sulfonic acid, which is referred to as very reactive, at room temperature, the desired compounds being obtained usually in good yields with relatively long reaction times. To reduce the reaction times, bis-(trifluoromethyl)methanol is proposed as solvent, but a mixture of mono- and difluorinated products is formed on use thereof. R. E. Banks et al. propose in J. Chem. Soc., chem. Commun. 1994, pages 343 to 344 the use of 1-chloromethyl-4-fluoro 1,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate for the fluorination of compounds with a xcex2-diketo structure, although the long reaction times make industrial use uneconomic. F. A. Davis et al. disclose in J. Org. Chem. 1995, 60, pages 4730 to 4737 the direct fluorination of xcex2-diketo compounds with N-fluorobenzenedisulfonimide at room temperature, there always being formation of mixtures of mono- and difluorinated products, and it being necessary to add water for predominant formation of monofluoro products. S. Stavber et al. describe in Teterahedron Letters, Vol. 37, No. 20, 1996, pages 3591 to 3594 the use of 1-hydroxy-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate for the fluorination of ketones at 80xc2x0 C. Finally, T. Umemoto et al. describe, in J. Org. Chem. 1998, 63, pages 3379-3385, the use of N,Nxe2x80x2-difluoro-2,2xe2x80x2-bipyridinium bistetrafluorobroate for the fluorination of compounds with a xcex2-diketo structure in acetonitrile, with relatively long reaction times being necessary despite the reflux temperature.
It is also known that optical induction is possible on xcex1-fluorination of ketones when the preformed enolates thereof are reacted with enantiopure N-fluorosultams, see, for example, E. Differding et al., Tetrahedron Letters, Vol. 29, No. 47, 1988, pages 6087 to 6090, Y. Takeuchi et al., J. Org. Chem. 1999, 64, pages 5708 to 5711, and F. A. Davis et al., J. Org. Chem. 1998, 63, pages 2273 to 2280.
T. Umemoto et al. describe, in J. Am. Chem. Soc. 1990, 112, pages 8563 to 8575, the addition of 0.4 equivalent of ZnCl2 or AlCl3 in the fluorination of activated methylene compounds with N-fluoro-2,4,6-trimethylpyridinium triflate. The reaction is carried out at elevated temperatures and the reaction times are relatively long despite this. Moreover mixtures of mono- and difluorinated compounds are formed. A. J. Poss et al. use 0.4 equivalent of ZnCl2 together with 0.4 equivalent of imidazole in the fluorination of ethyl cyclopentanonecarboxylate and 1,3-diphenyl-1,3-propanedione (see Tetrahedron Letters 40 (1999) pages 2673 to 2676). The reaction times are long and, in addition, elevated temperature is used, and difluorination cannot be suppressed.
R. D. Chambers et al. describe in Journal of Fluorine Chemistry 92 (1998), pages 45 to 52, the fluorination of activated methylene compounds with elemental fluorine in the presence of catalytic amounts of selected metal salts such as, for example, Cu, Ni, Cr, Mn, Fe, Co and Zn dinitrate, Cu dichloride, diacetate and sulfate. The yields which can be achieved are unsatisfactory, and a large proportion of difluorinated compounds is observed on fluorination of methylene groups.
Possibilities for the chorination, bromination and iodination of organic compounds, for example ketones, are described in xe2x80x9cThe Chemistry of Functional Groupsxe2x80x9d, Supplement D: Chapters 19 and 22, John Wiley and Sons Ltd. (1983), and Chapter 11, John Wiley and Sons Ltd. (1995).
The use of catalytic amounts of Lewis acids in the halogenation of activated methylene and methine compounds with electrophilic halogenation reagents has not yet been described. Nor has enantioselective halogenation of racemic methine compounds using catalytic amounts of optically active Lewis acids been disclosed either.
It has now been found, surprisingly, that catalytic amounts of certain titanium(IV) halides are able to speed up the halogenation of activated methylene and methine compounds with electrophilic halogenation reagents, and halogenation can be achieved with high yields in considerably shorter reaction times. In addition, the selectivity of monohalogenation of activated methylene compounds is considerably improved. It has also been found for the first time, surprisingly, that enantioselective halogenation of activated racemic methine compounds can also be carried out catalytically if titanium(IV) dihalides to which a chiral alkane-1,3-, -1,4- or -1,5-diolate is covalently bonded are used as catalyst. The halogenation can in fact take place under mild reaction conditions such as, for example, room temperature.
One aspect of the invention is a process for the halogenation of activated methylene and methine compounds with at least equimolar amounts of an electrophilic halogenation reagent, which comprises reacting said activated methylene and methine compounds in the presence of catalytic amounts of a titanium compound of the formula I or of a titanium compound of the formula II
R1TiX1X2X3xe2x80x83xe2x80x83(I), 
R2R3TiX1 X2xe2x80x83xe2x80x83(II), 
in which
R1 is chlorine, bromine or iodine, a substituted or unsubstituted cyclopentadienyl or indenyl, and X1, X2 and X3 are, independently of one another, chlorine, bromine or iodine, or X1, X2 and X3 are an organic sulfonate group where R1 is a substituted or unsubstituted cyclopentadienyl or indenyl;
R2 and R3 are a substituted or unsubstituted cyclopentadienyl or indenyl, R2 and R3 together are a substituted or unsubstituted and bridged or unbridged biscyclopentadienyl or bisindenyl, or R2 and R3 together are a substituted or unsubstituted 1,3-, 1,4- or 1,5-diolate, and X1 and X2 are, independently of one another, chlorine, bromine or iodine or an organic sulfonate group.
Activated methylene and methine compounds are to be understood as meaning for the purposes of the invention organic compounds to whose methylene or methine group at least two highly electron-attracting, or at least one highly electron-attracting and mesomerizing, or two electron-attracting and mesomerizing, groups are bonded. Examples of such groups are imine, keto, thioketo, aldehyde, carboxylate, carboxamide, nitrile, sulfoxide, sulfone, nitro, phosphonate, phosphine oxide and phosphonium groups. Preferred groups are imine, keto, carboxylate, carboxamide and nitrile groups. Highly electron-attracting groups are particularly preferably nitrile groups; the other aforementioned groups are electron-attracting and mesomerizing. Some examples of such groups of activated methylene and methine compounds are malonic diesters, malonamides, malononitrile, cyanoacetic esters and keto compounds; particular preference is given to xcex2-diketones and xcex2-keto carboxylic esters having 1 to 20 C atoms in the ester group. It has proved advantageous to employ for the halogenation those activated methylene and methine compounds which have a finite enol or enamine content and, among these, especially those able to form chelates with the titanium atom.
Examples of suitable activated methylene and methine compounds are saturated or unsaturated aliphatic, cycloaliphatic, heteroaliphatic and heterocycloaliphatic compounds having hetero atoms selected from the group of O, S and N and containing 2 to 30, preferably 2 to 20, and particularly preferably 2 to 16, C atoms. The cycloaliphatic and heterocycloaliphatic compounds may be mono- or polycyclic fused and/or bridged rings containing 3 to 16, preferably 3 to 12 and particularly preferably 4 to 8, ring members. Aromatic and/or heteroaromatic systems may also be fused to one or more rings. The compounds may be unsubstituted or substituted by xe2x80x94CN, xe2x80x94NH2, C1-C18alkyl, C1-C18alkoxy, C1-C8haloalkyl, xe2x80x94NH(C1-C12alkyl), xe2x80x94(C1-C12alkyl)2, xe2x80x94SO3M, xe2x80x94COOM, xe2x80x94COOH, xe2x80x94COOC1-C20alkyl or -phenyl or -benzyl or -diphenylmethyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NH(C1-C12alkyl), xe2x80x94COxe2x80x94N(C1-C12alkyl)2, C5-C12cycloalkyl, C5-C12cycloalkoxy, C5-C12heterocycloalkyl or C5-C12heterocycloalkoxy having 1 to 3 hetero atoms selected from the group of O, S and N, C6-C12 aryl or C6-C12aryloxy, C4-C11heteroaryl or C4-C11heteroaryloxy having 1 to 3 hetero atoms selected from the group of O, S and N, C7-C12aralkyl or C5-C12heteroaralkyl having 1 to 3 hetero atoms selected from the group of O, S and N, where M is Li, Na or K. Cyclic substituents may be unsubstituted or substituted, for example by halogen (preferably F, Cl or Br), xe2x80x94CN, C1-C8alkyl, C1-C4haloalkyl, C1-C8alkoxy or other aforementioned substituents. The compounds may contain one or more substituents.
Such activated methylene and methine compounds may, for example, have the formulae III and IV,
NCxe2x80x94CH(R4)xe2x80x94CNxe2x80x83xe2x80x83(III), 
R5xe2x80x94CH(R4)xe2x80x94C(xe2x95x90O)xe2x80x94R6xe2x80x83xe2x80x83(IV), 
in which R4 is hydrogen, linear or branched C1-C18alkyl, C2-C18alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl-C1-C6alkyl, C3-C12cycloalkenyl-C1-C6alkyl, C6-C18aryl, C7-C18aralkyl, C8-C18aralkenyl, or C3-C12heterocycloalkyl, C3-C12heterocycloalkenyl, C3-C12 heterocycloalkyl-C1-C6alkyl, C3-C12heterocycloalkenyl-C1-C6alkyl, C4-C18heteroaryl, C5-C18heteroaralkyl, each of which is bonded via a C atom and has hetero atoms selected from the group of O, S and N;
R5 is xe2x80x94CN or a xe2x80x94C(xe2x95x90O)xe2x80x94R7 group;
R6 independently has the same meanings as R4 or is linear or branched C1-C18alkoxy, C3-C12cycloalkoxy C3-C12cycloalkyl-C1-C6alkoxy, C6-C18aryloxy, C7-C18aralkyloxy, C3-C12heterocycloalkyloxy, C3-C12heterocycloalkyl-C1-C6alkyloxy, C4-C18heteroaryloxy, C5-C18heteroaralkyl having hetero atoms selected from the group of O, S and N;
R7 is linear or branched C1-C18alkyl, C2-C18alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl-C1-C6alkyl, C3-C12cycloalkenyl-C1-C6alkyl, C6-C18aryl, C7-C18aralkyl, or C3-C12heterocycloalkyl, C3-C12heterocycloalkenyl, C3-C12heterocycloalkyl-C1-C6alkyl, C3-C12heterocycloalkenyl-C1-C6alkyl, C4-C18heteroaryl, C5-C18heteroaralkyl, each of which is bonded via a C atom and has hetero atoms selected from the group of O, S and N, linear or branched C1-C18alkoxy, C3-C12cycloalkoxy, C3-C12cycloalkyl-C1-C6alkoxy, C6-C18aryloxy, C7-C18aralkyloxy, C3-C12heterocycloalkyloxy, C3-C12heterocycloalkyl-C1-C6alkyloxy, C4-C18heteroaryloxy, C5-C18heteroaralkyl having hetero atoms selected from the group of O, S and N;
R4 and R6 together with the group xe2x80x94Cxe2x80x94C(xe2x95x90O)xe2x80x94 to which they are bonded are an aliphatic or heteroaromatic, saturated or unsaturated, single or polycyclic ring which contains 3 to 18 ring members and to which aromatic or heteroaromatic rings may be fused;
R6 and R7 together with the group xe2x80x94(Oxe2x95x90)Cxe2x80x94Cxe2x80x94C(xe2x95x90O)xe2x80x94 to which they are bonded are an aliphatic or heteroaromatic, saturated or unsaturated, single or polycyclic ring which contains 3 to 18 ring members and to which aromatic or heteroaromatic rings may be fused; where R4, R5, R6 and R7 are unsubstituted or substituted as defined above for methylene and methine compounds.
If R4, R6 and R7 are alkyl, it preferably contains 1 to 12 and particularly preferably 1 to 8 C atoms. If R4, R6 and R7 are alkenyl, it preferably contains 2 to 12 and particularly preferably 2 to 8 C atoms. If R4, R6 and R7 are cycloalkyl or cycloalkenyl, the latter are preferably C3-C8cycloalkyl and C3-C8cycloalkenyl respectively. If R4, R6 and R7 are cycloalkylalkyl or cycloalkenylalkyl, the latter are preferably C3-C8cycloalkyl-C1-C4alkyl and C3-C8cycloalkenyl-C1-C4alkyl respectively. If R4, R6 and R7 are C6-C18aryl, C7-C18aralkyl, the latter are preferably C6-C14aryl, particularly preferably C6-C10aryl, and C6-C14aryl-C1-C6alkyl, and particularly preferably C6-C10aryl-C1-C4alkyl, respectively. If R4, R6 and R7 are heterocycloalkyl or heterocycloalkenyl, the latter are preferably C4-C8heterocycloalkyl and C4-C8 heterocycloalkenyl respectively. If R4, R6 and R7 are heterocycloalkylalkyl or heterocycloalkenylalkyl, the latter are preferably C4-C8heterocycloalkyl-C1-C4alkyl and C4-C8heterocycloalkenyl-C1-C4alkyl respectively. If R4, R6 and R7 are heteroaryl or heteroaralkyl, the latter are preferably C4-C14heteroaryl and particularly preferably C4-C10heteroaryl, and C4-C14heteroaryl-C1-C6alkyl and particularly preferably C4-C10heteroaryl-C1-C4alkyl, respectively. The same preference is applied to the oxy radicals. Heterocycles preferably contain 1 to 3 and particularly preferably one or two hetero atoms selected from the group of O, S and N.
If R4 and R6, or R6 and R7, together form a ring, this preferably contains 3 to 12 ring members. The ring may contain one or more hetero atoms, preferably 1 to 3 and particularly preferably 1 or 2 hetero atoms. It is very particularly preferred for R4 and R6 together and R6 and R7 to have the formula xe2x80x94(CH2)mxe2x80x94(O)nxe2x80x94 in which m is a number from 1 to 10 and n is 0 or 1.
Some examples of R4, R6 and R7 are indicated below, which also apply analogously to oxy radicals.
Examples of alkyl and alkenyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl and allyl. A preferred group is methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
Examples of cycloalkyl and cycloalkenyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and cyclopentenyl, cyclohexenyl and cyclohexadienyl. Particular preference is given to cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl and cyclohexadienyl.
Examples of cycloalkylalkyl and cycloalkenylalkyl are cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cyclohexenylmethyl.
Examples of aryl are naphthyl and, in particular, phenyl.
Examples of aralkyl and aralkenyl are benzyl, diphenylmethyl, naphthylmethyl, xcex2-phenylethyl, xcex2-phenylethenyl and phenylpropyl.
Examples of heterocycloalkyl and heterocycloalkenyl are pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl and piperanzinyl.
Examples of heterocycloalkylalkyl and heterocycloalkenylalkyl are pyrrolidinylmethyl or ethyl, or -propyl, pyrrolinylmethyl or -ethyl or -propyl, tetrahydrofuranylmethyl or -ethyl or propyl, dihydrofuranylmethyl or -ethyl or -propyl and piperazinylmethyl or -ethyl or -propyl.
Examples of heteroaryl are pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, benzofuranyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl.
Examples of heteroaralkyl are pyridinylmethyl or -ethyl or -propyl, pyrimidinylmethyl or -ethyl or -propyl, pyrrolylmethyl or -ethyl or -propyl, furanylmethyl or -ethyl or -propyl, imidazolylmethyl or -ethyl or -propyl, indolylmethyl or -ethyl or -propyl.
Large numbers of electrophilic halogenation reagents are known. Among the fluorination reagents, those most frequently used are inert gas fluorides, fluoroalkoxyfluorides, sulfonyl fluorides, N-fluorinated pyridinium salts, tertiary N-fluoroammonium salts, N-fluorinated amides and imides, FClO3 and F2 itself. A review of fluorination reagents is to be found, for example, in Chem. Rev. 1996, 96,1717-1736 by S. Rozen and in Chem. Rev. 1996, 96, 1737 to 1755 by G. Sankar Lal et al. Some fluorination reagents can be purchased.
Among the inert gas fluorides, particular mention should be made of xenon difluoride. An example of fluoroalkoxylfluorides is (CF3)2CFOF. Of the sulfonyl fluorides, CF3SO2F is frequently used. The N-fluorinated pyridinium salts are internal salts of pyridines and bipyridyls substituted by sulfo grups, or triflates or tetrafluoroborates. Among the amides, particular mention should be made of N-alkylated and N-fluorinated sulfonamides, carboxamides, lactams and sultams. N-fluorinated imides are, in particular, dicarboximides or disulfonimides.
Preference is given according to the invention to tertiary N-fluoroammonium salts, especially 1-substituted 4-fluoro-1,4-diazoniabicyclo[2,2,2]octane salts with complex anions, for example BF4, AsF6, PF6 or SbF6. Suitable substituents are C1-C4alkyl, C1-C4hydroxyalkyl and C1-C4haloalkyl. A specific example is 1-chloromethyl- or 1-hydroxymethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate (Selectfluor(trademark)), which is commercially available.
Large numbers of electrophilic chlorinating, brominating and iodinating agents are likewise known, and some of them are commercially available. Possibilities are Cl2, Br2 or I2 or interhalogen compounds, for example BrCl or ICl, and in particular N-chlorinated, N-brominated and N-iodinated dicarboximides or disulfonimides, lactams and sultams. Examples of such imides are succinimide, phthalimide, naphthalene-1,2-, -2,3- or 1,8-dicarboximide and biphenyl-2,2xe2x80x2-dicarboximide. Further examples are monoalkyl dihalides, dialkyl monohalides and N-chlorinated, N-brominated and N-iodinated N-alkyl- or N-arylcarboxamides and -sulfonamides.
X1, X2 and X3 in compounds of the formula I are preferably bromine and particularly preferably chlorine. Cyclopentadienyl and indenyl may, for example, be substituted by C1-C4alkyl, particularly methyl, C1-C4alkoxy, chlorine or bromine, trimethylsilyl, phenyl, benzyl, cyclohexyl, trimethylene and tetramethylene. Preferred examples are cyclopentadienyl, methylcyclopentadienyl, dimethylcyclopentadienyl, trimethylcyclopentadienyl, tetramethylcyclopentadienyl, pentamethylcyclopentadienyl and trimethylsilylcyclopentadienyl.
Examples of sulfonate groups are aromatic sulfonates such as phenylsulfonate, tosylate and, in particular, trifluoromethylsulfonate (triflate). Preferred titanium compounds of the formula I are titanium tetrachloride, titanium tetrabromide, cyclopentadienyltitanium trichloride and cyclopentadienyltitanium tribromide.
If R2 and R3 in formula II together are a bridged cyclopentadienyl or indenyl, the bridging group may be, for example, xe2x80x94Si(CH3)2- or C1-C4alkylene, preferably ethylene. Suitable substituents have been mentioned above for cyclopentadienyl. If X1 and X2 are halogen, they are preferably Br and, in particular, Cl. R2 and R3 are preferably a 1,3-, 1,4- or 1,5-diolate.
Diolates are understood as meaning for the purposes of the invention divalent radicals of diols whose hydroxyl groups are bonded in the 1,3, 1,4 or 1,5 positions of a substituted or unsubstituted C3, C4 or C5 chain in an open-chain, cyclic or cyclic-aliphatic compound. Corresponding 1,4-diolates are preferred, these also encompassing 1,1xe2x80x2-bicyclic hydrocarbons with hydroxyl groups bonded in the 2,2xe2x80x2 position. Large numbers of 1,3-, 1,4-or 1,5-diols for preparing the titanium diolate dihalides used as catalyst are known, and some of them can be purchased.
If R2 and R3 together are a substituted or unsubstituted 1,3-, 1,4- or 1 ,5-diolate, they are propane-1,3-, butane-1,4- and pentane-1,5-diolates, which are unsubstituted or substituted, for example by 1 to 6 or 1 to 3 substituents, or in which a C2 or C3 unit of the C chains form together with two substituents a 4- to 8-membered, preferably 5- to 7-membered, mono-, bi- or tricyclic hydrocarbon ring which is unsubstituted or substituted. Suitable 1,4-diolates may also be derived from unsubstituted or substituted bicyclic 2,2xe2x80x2-diols, for example biphenyl-2,2xe2x80x2-dioxy, dinaphthyl-2,2xe2x80x2-dioxy, bicyclohexyl-2,2xe2x80x2-dioxy and bicyclopentyl-2,2xe2x80x2-dioxy.
Examples of suitable substituents are halogen, C1-C8alkyl and preferably C1-C4alkyl, C3-C8cycloalkyl and preferably C5-C6cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl and preferably C5-C6cycloalkylmethyl or -ethyl, C6-C10aryl and preferably phenyl or naphthyl, C7-C12aralkyl and preferably benzyl and phenylethyl, and, bonded in the 2 or 3 position, C1-C8alkoxy and preferably C1-C4alkoxy, C3-C8cycloalkoxy and preferably C5-C6cycloalkoxy, C3-C8cycloalkyl-C1-C4alkoxy and preferably C5-C6cycloalkylmethoxy or -ethoxy, C6-C10aryloxy and preferably phenyloxy or naphthyloxy, C7-C12aralkyloxy and preferably benzyloxy and phenylethoxy, or, bonded in the 2,3 position and unsubstituted or substituted by a hydrocarbon radical as defined above, trimethylene, tetramethylene, ethylene-1,2-dioxy or methylenedioxy. Cyclic substituents may in turn be substituted, for example, by C1-C4alkyl, C1-C4alkoxy or halogen.
On use of activated racemic methine compounds in the process of the invention, optical inductions and enantioselective halogenations are surprisingly achieved when the titanium catalyst comprises an optically active diolate, in particular an optically active propane-1,3-, butane-1,4- or pentane-1 ,5-diolate as ligand. This is the first catalysed process for enantioselective halogenation. Optical yields of up to 85% ee and more can be achieved.
In a preferred embodiment, the process of the invention for enantioselective halogenation is carried out in the presence of catalytic amounts of titanium compounds of the formula II in which R2 and R3 together are an enantiopure substituted propane-1,3-, butane-1,4- or pentane-1,5-dioxy. Preferred titanium compounds of the formula II are those in which R2 and R3 together are enantiopure substituted butane-1 ,4-dioxy radicals, which induce particularly high optical yields as catalysts in the halogenation.
The butane-1,4-dioxy may, for example, have the formula V or VI 
in which Y1 and Y2 are a substituent, for example C1-C4alkyl, C1-C4alkoxy or halogen, and 5- or 6-membered carbocyclic rings can be fused to the benzene rings.
Butane-1,4-diolates which are more preferably used contain at least one stereogenic C atom. The stereogenic C atoms are preferably located in the 2 or in the 2 and 3 positions of the butane chain. The stereogenic C atoms may, however, also be located in the 1 or in the 1 and 4 positions of the butane chain. The C atoms in the 1 and 4 positions may be substituted by hydrocarbon radicals which preferably contain 1 to 12 and particularly preferably 1 to 8 C atoms. The C atoms in the 2 and 3 positions may be substituted by hydrocarbon radicals and/or by hydrocarbon oxy radicals which preferably contain 1 to 12 and particularly preferably 1 to 8 C atoms, it being possible for two substituents in the 2 and 3 positions to form together with the C atoms to which they are bonded a 3- to 8- and preferably a 5- or 6-membered carbocyclic ring, or a dioxolane ring.
The butane-1 ,4-diolates particularly preferably have the formula VII 
in which
Y3, Y4, Y5, Y6, Y7 and Y8 are, independently of one another, a hydrogen atom, C1-C8alkyl and preferably C1-C4alkyl, C3-C8cycloalkyl and preferably C5-C6cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl and preferably C5-C6cycloalkylmethyl or -ethyl, C6-C10aryl and preferably phenyl or naphthyl, C7-C12aralkyl and preferably benzyl and phenylethyl;
Y5 and Y6 are C1-C8alkoxy and preferably C1-C4alkoxy, C3-C8cycloalkoxy and preferably C5-C6cycloalkoxy, C3-C8cycloalkyl-C1-C4alkoxy and preferably C5-C6cycloalkylmethoxy or ethoxy, C6-C10aryloxy and preferably phenyloxy or naphthyloxy, C7-C12aralkyloxy and preferably benzyloxy and phenylethyloxy;
Y5 and Y6 are, together with the C atoms to which they are bonded, C5-C8cycloalkyl; or
Y5 and Y6 are, together with the C atoms to which they are bonded, the radical xe2x80x94Oxe2x80x94CY9Y10xe2x80x94Oxe2x80x94;
Y9 and Y10 are, independently of one another, a hydrogen atom, C1-C8alkyl and preferably C1-C4alkyl, C3-C8cycloalkyl and preferably C5-C6cycloalkyl, C3-C8cycloalkyl-C1-C4alkyl and preferably C5-C6cycloalkylmethyl or -ethyl, C6-C10aryl and preferably phenyl or naphthyl, C7-C12aralkyl and preferably benzyl and phenylethyl;
Y3, Y4, Y5, Y6, Y7, Y8, Y9 and Y10 are unsubstituted or substituted by halogen, C1-C4alkyl or C1-C4alkoxy;
with the proviso that at least one of Y3, Y4, Y5, Y6, Y7, Y8, Y9 and Y10 is one of said radicals.
The preferences and exemplary embodiments indicated above apply to the radicals.
Y5 and Y6 in formula VII are, together with the C atoms to which they are bonded, preferably C5-C8cycloalkyl or the radical xe2x80x94Oxe2x80x94CY9Y10xe2x80x94Oxe2x80x94.
Particularly preferred compounds of the formula VII are (4R,5R)- and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane, and (4R,5R)- and (4S,5S)-4,5-bis(di-1-naphthylhydroxymethyl)-2,2-dimethyldioxolane, which are commercially available.
Further examples of enantiopure diolates are those of the formulae 
The catalysts to be used according to the invention are known or can be obtained by methods known from the literature (for example Beck et al., Chimia 1991, 45, page 238 and D. Seebach et al., J. Org. Chem. 1995, 60, pages 1788 to 1799, and D. Seebach et al., Helvetica Chimica Acta, 82, (1999), pages 1829 to 1842) by, for example, reacting titanium dihalide diisopropoxide with diols. The catalysts can be prepared in situ and be used in the process of the invention, or the catalysts can be isolated and employed as such. Isolated catalysts may be in the form of solvates of solvents used for their preparation.
A catalytic amount may mean for the purposes of the invention 0.5 to 20 mol %, preferably 1 to 15 mol %, and particularly preferably 2 to 10 mol %, based on the activated methylene or methine compounds.
The halogenation reagents are generally used in equimolar amounts or a slight excess based on the activated methylene or methine compounds. It may be advantageous to add the fluorination reagent in portions or continuously during the reaction, especially in the monofluorination of activated methylene compounds.
The process can be carried out at temperatures from xe2x88x9240xc2x0 C. to 120xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C., and particularly preferably 0 to 80xc2x0 C. Lower temperatures are beneficial for the enantiomeric excess.
The process of the invention may be carried out with or without solvent. Examples of suitable solvents are aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated aliphatic hydrocarbons (methylene chloride, chloroform, di- and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane), ketones (acetone, methyl isobutyl ketone), carboxylic esters and lactones (ethyl and methyl acetates, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylacetamide, dimethylformamide), acyclic ureas (tetramethylurea) or cyclic ureas (dimethylimidazolidinone), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone), alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and nitrohydrocarbons (nitromethane). The solvents can be employed alone or in any suitable mixtures.
The process is preferably carried without solvent or in solvents such as N,N-dialkylated carboxamides and lactams, for example dimethylacetamide, dimethylformamide, N-methylpyrrolidone, and propylene carbonate, dimethyl sulfoxide, dioxane, acetonitrile, nitromethane or alcohols.
The process of the invention is preferably carried out with exclusion of water. It is expedient to dry the chemicals used, such as solvents, beforehand, or to add water-binding agents such as molecular sieves.
The isolation and purification of the halogenated compounds can take place by methods known per se, for example distillation, crystallization, recrystallization and chromatographic methods.
The halogenated compounds obtainable according to the invention are valuable intermediates for preparing pesticides and active pharmaceutical ingredients. Thus, W. J. Middleton describes, in J. of Fluorine Chemistry 100 (1999), pages 207-216, the efficacy of 3-fluorodiazepam, a derivative of Valium(copyright). R. Filler et al. describe, in Biomedicinal Aspects of Fluorine Chemistry, Elsevier Biomedical Press (Amsterdam-New York-Oxford 1982), the efficacy of fluorinated active ingredients, for example 4-fluorofarnesol, as insect attracter. Chlorinated, brominated and iodinated compounds are valuable intermediates which can easily be derivatized, for example to give OH, NH2, alkoxy or alkyl derivatives. In the case of enantiopure intermediates this makes it possible to prepare the required stereoisomer specifically with inversion at the stereogenic C atom.
The following examples illustrate the invention in more detail. The following abbreviations are used:
TLC: thin-layer chromatography, FC: flash chromatography, MeCN: acetonitrile; DME: 1,2-dimethoxyethane, MS: molecular sieves, RT: room temperature, RE: rotary evaporator, HV: high vacuum, TBME: tert-butyl methyl ether.
F-TEDA: 1-chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo[2,2,2]octane bistetrafluoroborate (Selectfluor(copyright))
NFSI: N-fluorodibenzenesulfonimide,
NCS: N-chlorosuccinimide
R-TADDOL: (4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane
xcex1-Naphthyl-TADDOL: (4R-trans)-2,2,-dimethyl-xcex1,xcex1,xcex1xe2x80x2,xcex1xe2x80x2-tetra(1-naphthyl)-1,3-dioxolane-4,5-dimethanol
xcex2-Naphthyl-TADDOL: (xe2x88x92)-2,3-O-isopropylidene-1,1,4,4-tetra(2-naphthyl)-L-threitol
R-Binol: R(+)-1,1xe2x80x2-bi(2-naphthol)
A) Preparation of Catalysts